The LPS hyporesponsive C3H/HeJ mouse strain has been utilized to help elucidate the mechanism of action of LPS. These mice possess a mutation in a single autosomal gene which results in an abnormal tolerance to the effects of LPS in vivo and is expressed in the T and B lymphocytes, macrophages (M0) and fibroblasts. Additionally, M0 Fc-mediated phagocytosis is abnormal, suggesting a defect in M0 differentially. In vivo, the LPS defect in C3H/HeJ mice can be partially reversed by preinfection with BCG, a potent immunostimulant. In vitro, the C3H/HeJ M0 LPS and phagocytic defects can be reversed by treatment with lymphokine-rich, Con A-stimulated, spleen cell supernatant and the phagocytic defect by cAMP agonists. Furthermore, coculture of C3H/HeJ M0 with purified T lymphocytes derived from LPS responsive animals (including BCG-infected C3H/HeJ mice) results in the production of interleukin-1 (IL-1) by the M0. The systemic effects of endotoxins are mediated to a great extent by acute phase reactants such as prostaglandins, IL-1 and serum amyloid A (SAA). An LPS-stimulated monokine has been shown to stimulate hepatocytes to produce SAA. Thus the capacity to respond to LPS is required for normal macrophage differentiation, for the ability to produce monokines which in turn induce SAA production and/or other symptoms of endotoxicity.